The use of monoclonal antibodies (mAbs) in passive immunotherapy (PI) against Alzheimer's disease (AD) is emerging as a potentially useful therapeutic approach. The phase II clinical trials conducted by the ELAN corporation showed that their Abs were effective only against subpopulation groups of people, making it necessary to obtain a wide repertoire of Abs to treat AD. We have sub pM mAbs called PFA1 and PFA2 raised against the protofibrils of Aâ that recognizes various aggregate and soluble forms of Aâ. Initial, in vivo characterization of PFA1 in triple transgenic mice (3xTg-AD) shows up to a 30% lowering of amyloid burden. In the current proposal, we will conduct a more comprehensive study with a larger group of mice to assess the suitability of this Ab for future clinical studies. There is mounting evidence pointing to the importance of the Aâ dimer in AD pathology. Producing non-covalent stable Aâ dimers for immunization has been quite challenging. We have developed conditions for maintaining non-covalent Aâ dimers. In our attempt to generate a wide repertoire of Abs, we will immunize mice with stable Aâ dimers.